1. Polysaccharide deacetylases serve as new targets for the design of inhibitors against Bacillus anthracis and Bacillus cereus.
- Author
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Balomenou S, Koutsioulis D, Tomatsidou A, Tzanodaskalaki M, Petratos K, and Bouriotis V
- Subjects
- Amidohydrolases metabolism, Amino Acid Sequence, Anti-Bacterial Agents chemical synthesis, Bacillus anthracis enzymology, Bacillus cereus enzymology, Bacterial Proteins metabolism, Binding Sites, Catalytic Domain, Enzyme Inhibitors pharmacology, Hydroxamic Acids chemical synthesis, Hydroxamic Acids chemistry, Hydroxamic Acids pharmacology, Microbial Sensitivity Tests, Molecular Dynamics Simulation, Sequence Alignment, Amidohydrolases antagonists & inhibitors, Anti-Bacterial Agents pharmacology, Bacillus anthracis drug effects, Bacillus cereus drug effects, Bacterial Proteins antagonists & inhibitors, Drug Design, Enzyme Inhibitors chemistry
- Abstract
Peptidoglycan N-acetylglucosamine (GlcNAc) deacetylases (PGNGdacs) from bacterial pathogens are validated targets for the development of novel antimicrobial agents. In this study we examined the in vitro inhibition of hydroxamate ligand N-hydroxy-4-(naphthalene-1-yl)benzamide (NHNB), a selective inhibitor of histone deacetylases-8 (HDAC8), against two PGNGdacs namely BC1974 and BC1960 from B. cereus, highly homologous to BA1977 and BA1961 of B. anthracis, respectively. Kinetic analysis showed that this compound functions as a competitive inhibitor of both enzymes with apparent K
i 's of 8.7 μM (for BC1974) and 66 μM (for BC1960), providing thus the most potent CE4 inhibitor reported to date. NHNB was tested in antibacterial assays and showed bactericidal activity against both examined pathogens acting as a multi-target drug. This compound can serve as lead for the development of inhibitors targeting the conserved active sites of the multiple polysaccharide deacetylases (PDAs) of both pathogens., (Copyright © 2018 Elsevier Ltd. All rights reserved.)- Published
- 2018
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